The entry of HIV-1 into permissible cells involves a complex series of events, orchestrated by the viral envelope glycoprotein complex, the only viral components exposed on the virion surface. As the only viral products accessible to the host cell immune system, the Env glycoproteins (gp120 and gp41) have evolved several strategies to mask functionally important regions from the neutralizing antibody response. These include the presence of surface-exposed variable loops on gp120, a high degree of glycosylation, the lability and defectiveness of many envelope glycoprotein spikes (possible immunologic decoys), and conformational flexibility.
The Env complex is organized on the virion surface as trimeric spikes, composed of three gp120 molecules noncovalently linked to three gp41 molecules. The heavily glycosylated surface gp120 contains a core composed of conserved regions (C1 to C5) and hypervariable regions that are mostly disulfide-constrained, surface-exposed loop structures (V1 to V5) that retain a large degree of flexibility. The transmembrane glycoprotein gp41 contains the fusion peptide, which is inserted into the membrane of the target cell as well as two heptad repeat (HR) domains (aminoterminal or HR1 and carboxyterminal or HR2) that are implicated in the formation of a six-helix-bundle fusion intermediate through a conformational change following receptor interaction.
HIV-1, unlike pH dependent viruses, uses receptor engagement to elicit the conformational changes in the viral envelope glycoproteins required for fusion. The receptor used by HIV-1 is CD4. Many studies have demonstrated that CD4 engagement induces significant changes in gp120. These changes in gp120 allow chemokine receptor binding and also result in the formation and/or exposure of the HR1 coiled coil on gp41. The effects of gp120 binding to CD4, in conjunction with binding to the chemokine receptor, initiate the conformational transitions required for membrane fusion. Therefore, both intra- and intermolecular interactions coordinate to facilitate the transduction of receptor-binding signals between the components of the Env complex and ultimately result in fusion.
HIV-1 infection usually occurs only after two sequential and specific binding steps: first, to the CD4 antigen present in CD4+ T cells, monocyte/macrophages, and other immune/nonimmune cells; second, to a member of the chemokine receptor subfamily, within the large G protein-coupled family of receptors, mainly CCR5 and/or CXCR4. Binding of CD4 or other ligands to the Phe43 cavity of gp120 is often accompanied by a conformational rearrangement that exposes coreceptor binding surfaces. Further, ligands binding to gp120 at sites other than the Phe43 cavity can elicit positive or negative conformational changes, enhancing or limiting the accessibility of the co-receptor binding site.
Because of the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. An attractive intervention point for such new inhibitors is viral entry into permissible cells. However, this strategy remains almost completely unexploited. In the HIV-1 entry field, only two main inhibitor chemotypes predominate: the NBD-556 analogues (Zhao et al., 2005, Virology, 339:215-225) and the BMS-377806 analogues (Wang et al., 2003, J. Med. Chem. 46:4236-4239). The NBD-556 analogues suffer from the propensity to elicit the same conformational rearragements as CD4, limiting their current use, as they could promote infection of cells not usually permissible to HIV-1 infection. Similarly, the BMS-377806 analogues, although very potent and with no promotion of infection of CD4 negative cells, have poor solubility and oral bioavailability. Therefore, given the enormous potential of small molecule entry inhibitors, new chemotypes with high potency and improved drug-like qualities are highly desirable.
Compounds with distinct chemical structures can bind at the same biological site and elicit the same agonist/antagonist effect. As such, binding sites must recognize specific attributes of the compound/molecule that lead to its biological activity and not specific structural detail, i.e., the regions of positive and negative charge, lipophilicity, and the spatial arrangement of these regions. A new variation of this pharmacophore approach is the use of FieldPoints, which are the local extrema of these potential and shape surfaces. FieldPoints can be used to describe and compare biologically active molecules and to scaffold-hop. To date, the piperazine-based entry inhibitors as first described by Bristol-Myers Squibb (Wang et al., 2003, J. Med. Chem. 46:4236-4239) are the most broadly acting and potent HIV-1 entry inhibitors. This indicates that the binding site for these compounds, although currently not well described, is broadly conserved and available for targeting on the virion.
There is a need in the art for novel compositions that are useful for the treatment of HIV-1 infection in a mammal. The present invention addresses this unmet need.